Organic reactions with CO generating materials

ABSTRACT

The present invention is drawn to a method of performing a one-pot organic reactions including carbon monoxide as reactant, without the use of an external CO gas source, wherein a reaction mixture containing a solid or liquid CO releasing compound, a non-metal substrate and a metal catalyst is exposed to an energy source to release carbon monoxide from the CO releasing compound and wherein carbon atoms of the released carbon monoxide form a bond with the non-metal substrate compound. The present invention is further drawn to a method of preparing chemical libraries and a kit for organic reactions.

FIELD OF THE INVENTION

The present invention relates to the use of a material generating CO insitu as a non-catalysing precursor of carbon monoxide in one-pot organicreactions, such as carbonylation and hydroformylation reactions. Thematerial regenerating CO in situ liberates the carbon monoxide intosolution upon exposure of the reaction medium to a form of energy andresults in the covalent bond formation between the carbon of the carbonmonoxide with a non-metal substrate. The present invention furtherrelates to microwave assisted reactions using a non-catalysing materialgenerating CO in situ as a non-catalysing precursor of carbon monoxideso as to result in the covalent bond formation between the carbon of thecarbon monoxide with a non-metal substrate. The use of microwave energyin carbon monoxide insertion reactions in combination with anon-catalysing condensed precursor of carbon monoxide provides a meansof preparing chemical libraries via combinatorial chemistry.

BACKGROUND OF THE INVENTION

Carbon monoxide is a very versatile and common reagent in organicsynthesis. Apart from its common use as reducing agent, severalmetal-catalysed carbonylative applications have been developed duringthe last 50 years.

In these reactions, gaseous CO is frequently used as the CO source. Acatalyst “shuttles” CO from the gas phase to the substrate where a COmolecule is inserted to said substrate. The catalyst must have certainproperties in order to shuttle CO(g). The catalyst should have aspontaneous affinity for CO; otherwise it will not bond to it.

The gaseous carbon monoxide source is conventionally used in reactionssuch as (a) palladium-catalysed carbonylations of aryl halides to ancarboxylic acid or ester with water or an alcohol or to an amide with anamine; (b) metal-catalysed three component cross-coupling reactionsbetween an arylmetal reagent, carbon monoxide gas and an aryl halide,often at high pressures to avoid side products (e.g. direct coupling);and (c) metal catalysed hydroformylation reactions. Still othermethodologies (for example Ishiyama et al, Tetrahedron Letters, 1993,34, 7595) resolve cross-reactivity problems by derivatizing thenucleophile or electrophile.

In one conventional method of performing carbonylation reactions, onestarts with a metal carbonyl as a pre-catalyst (which by its veryexistence affirms the affinity of the metal for CO). In broad terms, thefollowing sequence unfolds: irradiation by UV-light or thermal heatingmakes one CO dissociate from the metal carbonyl pre-catalyst liberatinga free site on the metal; the substrate inserts itself to saidfree-site; a CO molecule originally bonded to the metal inserts to thesubstrate; the (carbonylated) product is eliminated generating two freesites; these sites are refilled with one new substrate molecule and COfrom the gas phase; the cycle repeats itself until the CO or thesubstrate is fully consumed, or the catalyst is inactivated by, forexample, poisoning. A schematic mechanism for these reactions isillustrated in FIG. 1.

In 1969, Corey (Corey E. J., Hegedus, L. S., Journal of the AmericanChemical Society, 1969, 91(5), 1233-1234) published early seminar workon the carboxylation of certain activated substrates (organic halides)with Ni(CO)₄ as catalyst and CO-source. Nickel carbonyl is extremelytoxic and is a very inefficient catalyst. In fact, 600% metal carbonylcatalyst is required for the reaction to proceed. The reactions werebase catalysed and relied on the tendency of metal carbonyls to formmore electropositive anionic species under basic conditions. Theseconditions are appropriate exclusively for only a small number ofactivated systems. Moreover, the use of an external pressure of carbonmonoxide gas, even at high pressures, does not improve the efficiency ofthe catalyst since the external carbon monoxide retards the formation offree sites on the metal Ni.

A recent methodology for carbonylation reactions, hydrocarbonylationreactions or carbonylation cross-coupling reactions (Johansson et al,Organometallics, 1995, 14, 3897) relied on pre-forming a complex betweenthe CO-source and the substrate. This method is limited in that itrequires the pre-formation of the metal carbonyl complex with asubstrate as well as the pre-activation of said substrate.

It is known that DMF decomposes into carbon monoxide and dimethylaminewhen heated, cf. e.g. Perrin, D. D., Aremarego, W. L. F. and Perrin, D.R., “Purification of Laboratory Chemicals”, 3rd, Pergamon Press, 1988,pp. 157-158. DMF has also been used for dimethylamination of acidchlorides, cf. Lee, W. S., Park, K. H. and Yoon, Y. -J., “SyntheticCommunications” 30(23), pp. 42414245 (2000).

In a recent article (Schnyder, A., Beller, M., Mehitretter, G., Nsenda,T., Studer, M. and Indolese, A. F., J. Org. Chem. 2001, 66, 4311-4315 anaminocarbonyl reaction for preparation of primary amides is described.In said aminocarbonylation reaction carbon monoxide gas is used as theCO source and reactions with formamide and dimethyl formamide in thepresence of imidazole as the base are described. The highest yields wereobtained at temperatures between 90 and 120° C. while at highertemperature (150° C.) nonidentified side products were formed. It isalso underlined that CO is a pre-requisite for the formation of aroylspecies and that the reaction does not proceed without a CO atmosphere.Different bases were also tested and the fastest reactions were obtainedwith 4-(dimethylamino) pyridine (DMAP) and 4-pyrrolidinopyridine. A highyield was also obtained with imidazole.

SUMMARY OF THE INVENTION

The present invention relates to a method for performing a one-potorganic reaction which includes carbon monoxide as a reactant withoutthe use of an external CO gas source, which comprises preparing areaction mixture containing a non-catalysing, solid or liquid, i.e.non-gaseous, CO releasing compound generating CO in situ; and exposingsaid reaction mixture to an energy source affording liberation of carbonmonoxide from said non-catalysing CO releasing compound, wherein carbonmonoxide is involved in said reaction such that the carbon of saidcarbon monoxide is involved in bond formation to a non-metal during saidorganic reaction.

A one-pot reaction in this context means addition of all startingmaterials, reactants and catalyst(s) before the start of the reaction byexposure to an energy source such as heating or microwaves.

The invention further relates to a method for performingmicrowave-assisted reactions comprising the steps of preparing areaction mixture comprising a non-catalysing, non-gaseous compoundreleasing CO in situ; and exposing said reaction mixture to sufficientmicrowave energy to afford liberation of carbon monoxide from saidnon-catalysing compound releasing CO in situ, wherein the carbonmonoxide is involved in said reaction such that the carbon of saidcarbon monoxide is involved in bond formation to a non-metal during saidorganic reaction.

The invention further relates to method of preparing chemical librariescomprising the steps of preparing a reaction mixture comprising anon-catalysing, solid or liquid CO compound releasing CO in situ, anon-metal substrate compound and a metal catalyst; and exposing saidreaction mixture to an energy source affording liberation of carbonmonoxide from said non-catalysing compound releasing CO in situ, whereincarbon monoxide is involved in said reaction such that the carbon ofsaid carbon monoxide is involved in bond formation to a non-metal duringsaid organic reaction.

A suitable non-catalysing solid compound releasing CO in situ is a metalcarbonyl of the general formula IM_(x)(CO)_(y)  Iwherein M is a metal, x is an integer and y is an integer.

A suitable non-catalysing liquid compound releasing CO in situ which issuitable in the method according to the present invention is a formamideof the general formula IIHCONR₁R₂  IIwherein R₁ and R₂ independently can be H, optionally substituted, linearor branched alkyl, aryl or alkylaryl.

The present invention further relates to a kit for organic reactionshaving CO as reactant which include a one or more solid or liquid COreleasing compounds, selected from metal carbonyls of the generalformula I,M_(x)(CO)_(y)wherein M is a metal, x is an integer, y is an integer, or formamides ofthe general formula II,HCONR₁R₂wherein R₁ and R₂ independently can be H, or an optionally substituted,linear or branched alkyl, aryl or alkylaryl group. The reagents of thekit will be placed into a container or containers (eg a vial, test tube,reagent bottle, etc) either alone, or if appropriate, with otheringredients. One or more of these containers which contain the reagentsfor practicing the invention can be placed into an outer container (eg abox). The kit may contain instructions for using the reagents and inparticular may contain instructions for carrying out a method accordingto the present invention.

DESCRIPTION OF THE INVENTION

Carbonylation induces a polar A-C(O)—B link between a scaffold and thesubstituent. By the choice of CO-derivative (e.g. C(O)—B, B═OR ester)the polarity can be tuned to fit the specific requirements and by thechoice of substituents (A,B) the spatial arrangement can be tuned. Anamide (a type of carbonyl), for instance, is highly stable, possesssimilarity to biological systems, and are able to participate inhydrogen bonding as both a donor and/or acceptor.

Thus, in addition to the obvious structural changes to a molecule uponcarbonylation, many physical attributes can be altered by carbonylation.In medicinal chemistry and in the construction of a biologically activeagents in general, one must consider not only the spatial orelectrostatic specific interaction with the targets, but also theadministration, distribution, metabolism and elimination of thecompound. Highly polar substances do not readily pass through theepithelium to enter the blood stream whereas lipophilic compounds havelow solubility and tend to accumulate in the liver where they aredestroyed. Carbonylation, by introducing a polar —C(O)— unit,substituent (A,B) or apolar substituent (A,B) may serve to tune thepolarity of an agent in order to improve its bioavailabilty, itsactivity and even its specificity. The present method thus serves as apowerful tool for the field of medicinal chemistry as well as in thefields of agrochemistry, food chemistry, colour chemistry andfragrance/flavour chemistry.

Advances in combinatorial chemistry relate to improved methods ofhandling as well as to improved techniques in performing a chemicalreaction. In its applications, the focus is commonly placed on easy orautomated handling of a large amount of samples rather than to inertprecautions. The development of fast, reliable and convenient protocolsis therefore important in the field of combinatorial chemistry. Chemicallibraries may be prepared through the emerging field of combinatorialchemistry. The method of the present invention is very amenable to thefield of combinatorial chemistry and to the preparation of chemicallibraries.

For clarity purposes, it is best to explain at this stage that carbonmonoxide acts as an electrophile in these types of reactions. At thestart of a reaction, the substrate acts as an electrophile and thecatalyst acts as a nucleophile (once activated). However, once thesubstrate-catalyst complex is formed, the substrate component of thecomplex acts as a nucleophile to carbon monoxide.

The present invention provides a method of performing organic reactionssuch as carbonylation reactions, hydrocarbonylation reactions,hydroformylation reactions, carbonylation cross-coupling reactions suchas cycloaddition reactions as well as reactions based on similarchemical principles with at least one advantage of allowing forflexibility in selecting the carbon monoxide source from CO releasingcompound independently from selecting a reagent such as the nucleophile.

This methodology is surprisingly applicable to a variety of reactiontypes providing similar or better yields to conventional methodology.Moreover, typically less side products are formed thus facilitatingpurification. In accordance with the present invention relatively highyields of the desired reaction can be achieved in a short period oftime. In some difficult reactions yields of 35% or higher or 50% orhigher are considered “high”. In other easier reactions yields as highas 80% or greater or 90% or greater and approaching 100% can beachieved.

The liquid or solid material generating CO in situ serves as the sourceof carbon monoxide. This offers a further advantage of avoiding the useof pressurised cylinders to generate the gas thus offering a pragmaticadvantage to conventional methods. The present invention has as anobject the use of a CO releasing compound in organic reactions.

Critically, the method according to the present invention is a one-stepprocess. This compares favourably to other methodologies not usinggaseous carbon monoxide, wherein the 3-step process of complexation ofthe metal carbonyl to a reagent, carbonylation, and decomplexation ofthe reaction mixture, usually via photolysis, is typically required(supra or Johansson et al, Organometallics, 1995, 14, 3897).

The present invention has overcome the trouble of using gas in organicreactions such as carbonylations by applying a CO releasing compound,such as the metal carbonyl M_(x)(CO)_(y) or the formamide HCONR₁R₂,which upon perturbation liberates enough gas in situ for the reaction totake place.

Moreover, the toxicity associated with the handling of CO has beenovercome by the convenient method of the present invention.

The term “optionally substituted”, in connection with the terms “aryl”,“heteroaryl”, “cycloalkyl”, “heterocyclyl”, “alkyl”, “alkoxy”,“alkenyl”, “olefin” and “alkynyl”, is intended to mean that the group inquestion may be substituted one or several times, such as 1 to 5 times,or 1 to 4 times, preferably 1 to 3 times, with a “substituent”, namelywith one or more groups selected from C₁₋₆-alkyl, C₁₋₆-alkoxyl, oxo(which when present may be represented in the tautomeric enol form),carboxyl, amino (which when present may be represented in animine-enamine tautomeric form), hydroxyl (which when present mayberepresented in an enol system may be represented in the tautomeric ketoform), halogen, such as per- or polyfluorinates, nitro, sulphono,sulphanyl, C₁₋₆-carboxyl, C₁₋₆-alkoxycarbonyl, C₁₋₆-alkylcarbonyl,formyl, aryl, aryloxy, aryloxycarbonyl, arylcarbonyl, heteroaryl, mono-and di(C₁₋₆-alkyl)amino; carbamoyl, mono- anddi(C₁₋₆-alkyl)aminocarbonyl, amino-C₁₋₆-alkyl-aminocarbonyl, mono- anddi(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl, C₁₋₆-alkylcarbonylamino,cyano, guanidino, carbamido, C₁₋₆-alkanoyloxy, C₁₋₆-alkylsulphonyloxy,dihalogen-C₁₋₆alkyl, trihalogen-C₁₋₆alkyl, or per- or polyfluorinatedanalogues thereof. The reactivity of the substituents may be attenuatedor masked by the use of protective groups known the person skilled inthe art.

The term “alkyl” is intended to mean a linear, cyclic (cycloalkyl) orbranched saturated hydrocarbon group having from one to twelve carbonatoms, such as methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, isopentyl,neopentyl, cyclopentyl, hexyl, cyclohexyl, heptyl, cycloheptyl, and soforth. The term “alkyl” is also intended to mean alkoxy groups such asC₁₋₆alkyl-oxy such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy,hexoxy and heptoxy. The term “alkyl” is also intended to mean“heterocyclyl” wherein a ring comprising three-, four-, five-, six-seven-, and eight-saturated carbon atoms together with from 1 to 3heteroatoms form said ring. The heteroatoms are independently selectedfrom oxygen, sulphur, and nitrogen.

Examples of typical “heterocyclyl” groups are 2H-thipyran, 3H-thipyran,4H-thipyran, tetrahydrothiopyran, 2H-pyran, 4H-pyrane, tetrahydropyran,piperidine, 1,2-dithiin, 1,2-dithiane, 1,3-dithiin, 1,3-dithiane,1,4-dithiin, 1,4-dithiane, 1,2-dioxin, 1,2-dioxane, 1,3-dioxin,1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,2-oxathiin,1,2-oxathiane, 4H-1,3-oxathiin, 1,3-oxathiane, 1,4-oxathiin,1,4-oxathiane, 2H-1,2-thiazine, tetrahydro-1,2-thiazine,2H-1,3-thiazine, 4H-1,3-thiazine, 5,6-dihydro-4H-thiazine,4H-1,4-thiazine, tetrahydro-1,4-thiazine, 2H-1,2-oxazine,4H-1,2-oxazine, 6H-1,2-oxazine, 2H1,3-oxazine, 4H-1,3-oxazine,4H-1,4-oxazine, morpholine, trioxane, 4H-1,2,3-trithiin,1,2,3-trithiane, 1,3,5-trithiane, hexahydro-1,3,5-triazine,tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine,pyrrolidone, pyrrolidione, pyrazoline, pyrazolidine, imidazoline,imidazolidine, 1,2-dioxole, 1,2-dioxolane, 1,3-dioxole, 1,3-dioxolane,3H-1,2-dithiole, 1,2-dithiolane, 1,3-dithiole, 1,3-dithiolane,isoxazoline, isoxazolidine, oxazoline, oxazolidine, thiazoline,thiozolidine, 3H-1,2-oxathiole, 1,2-oxathiolane, 5H-1,2-oxathiole,1,3-oxathiole, 1,3-oxathiolane, 1,2,3-trithiole, 1,2,3-trithiolane,1,2,4-trithiolane, 1,2,3-trioxole, 1,2,3-trioxolane, 1,2,4-trioxolane,1,2,3-triazoline and 1,2,3-triazolidine.

The term “aryl” is intended to mean a carbocyclic or heterocyclicaromatic ring (heteroaryl) or ring system. Moreover, the term “aryl”includes fused ring systems wherein at least two aryl rings, or at leastone aryl and at cyloalkyl ring share at least one chemical bond.Examples of “aryl” rings include optionally substituted phenyl,naphthalenyl, phenanthrenyl, anthracenyl, acenaphthylenyl, tetralinyl,fluorenyl, indenyl, indolyl, coumaranyl, coumarinyl, chromanyl,isochromanyl, and azulenyl. A preferred aryl group is phenyl.

A heteroaryl or heteraromatic ring is intended to mean an aryl where oneor more carbon atoms in an aromatic ring have been replaced with one ormore heteroatoms selected from the group comprising nitrogen, sulphur,and oxygen. Furthermore, in the present context, the term “heteroaryl”comprises fused ring systems wherein at least one aryl ring and at leastone heteroaryl ring, at least two heteroaryls, at least one heteroaryland at least one heterocyclyl, or at least one heteroaryl and at leastone C₃₋₈-cycloalkyl share at least one chemical bond, such as twochemical bonds.

Examples of heteroaryl rings may be selected from the group comprisingof optionally substituted, such as mono-, di-, tri-, ortetra-substituted furanyl, thiophenyl, pyrrolyl, phenoxazonyl, oxazolyl,thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, isoxazolyl, imidazolylisothiazolyl, oxadiazolyl, furazanyl, triazolyl, thiadiazolyl,piperidinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyland triazinyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl,benzopyrazolyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl,quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinylthienofuranyl,carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl andthianthrenyl.

The term “olefin” or “alkenyl” is intended to mean a linear, cyclic, orbranched hydrocarbon group having from two to eight carbon atoms whereinat least two said carbons are linked via a double bond. Examples ofC₂₋₈-alkenyl groups include olefins such as allyl, homo-allyl, vinyl,crotyl, butenyl, pentenyl, hexenyl, heptenyl and octenyl. Examples ofC₂₋₈-alkenyl groups with more than one double bond include butadienyl,pentadienyl, hexadienyl, heptadienyl, hexatrienyl, heptatrienyl andoctatrienyl groups as well as branched forms of these.

Examples of cyclic olefins include cyclopropene, cyclobutene,cyclobutadiene, cyclopentene, cyclopentadiene, cyclohexene,1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptene,1,2-cycloheptadiene, 1,3-cycloheptadiene, 1,4-cycloheptadiene and 1,3,5cycloheptatriene.

The terms “alkyne”, “propargylic” and “alkynyl” are intended to meanlinear, cyclic or branched hydrocarbon groups containing from two toeight carbon atoms wherein at least two said carbons are linked via atriple bond. Examples of C₂₋₈-alkynyl groups include acetylene,propynyl, butynyl, pentynyl, hexynyl, heptynyl and octynyl groups aswell as branched forms of these.

The term “alkynyl” is also intended to mean enynes, such as conjugatedenynes, wherein an olefin and alkyne are linked by a single carbon bond.

The term “halogen” includes fluorine, chlorine, bromine and iodine andis also intended to mean per- or polyfluorinated sulfonated esters.

The method according to the present invention is applicable to a varietyof reaction types known to the person skilled in the art as well as tosubstrates not considered by conventional methodologies to be veryamenable to carbonylation reactions. The method of the present inventionrelates to all reactions wherein CO forms a bond to the substrate asknown to the skilled artisan, such as those reviewed in Beller et al,Progress in hydroformylation and carbonylation reactions, Journal ofMolecular Catalysis A, 1995, 104, 17-85 and in Transition Metal AlkylComplexes: Oxidative Addition and Insertion, Soderberg, B. C.,Comprehensive Organometallic Chemistry II, Hegedus, L. S. Volume Ed.Abel, E. W.; Stone, F. G. A.; Wilkinson, G. Eds.; Pergamon Press: Oxford1995; vol. 12, pp. 259.

In the method of the invention, when using the metal carbonyl compoundas the CO source the metal carbonyl is not pre-complexed with or bondedto the non-metal to which the carbon of carbon monoxide bonds to duringthe reaction prior to preparing said reaction mixture.

Typical reaction types, wherein the present method is anticipated to beapplicable, are furthermore illustrated by the non-limiting series ofreaction types I-VI:

Type I reactions involve carbonylation of an activated substrate such asan aryl (Ar), such a phenyl, benzyl, or heteroaryl; an alkyl such asC₁₋₁₂-alkyl; an alkenyl, such as C₂₋₁₂-alkenyl; or an alkynyl group suchas C₂₋₁₂-alkynyl, each of which may be optionally substituted and eachof which is activated with X which may be, for example, halogen,mesylate, triflate, phosphonate, phosphine (in the substrate form of[ArPPh₃]⁺), tosylate, diazo, —NH₂ (which is in situ diazoated),hypervalent iodine, or boronic acid.

In this reaction type, the carbonylation occurs at the activated carbon.The term “activated” is intended to mean that the carbon atom of thesubstrate with which the carbon atom of carbon monoxide bonds to duringthe reaction, shares, at the onset of the reaction, a bond with a groupor atom which has a higher bond dissociation energy than acarbon-hydrogen bond.

For clarity purposes, it is best to re-state that in these types ofreactions, the aryl-X or alk-X acts as an electrophile, the Pd-catalystis a nucleophile (once activated). However, once the Ar—Pd—X is formed,the Ar or alk is nucleophilic and the Pd is electrophilic. Carbonmonoxide acts as an electrophile.

In addition to the examples listed above which serve to activate thesubstrate, the activating group may be an epoxide or an aziridine. Insuch cases, the product is typically the corresponding lactone orβ-lactam, respectively.

In relation to the nucleophile, R and R′ may be independently selectedfrom the group comprising of hydrogen, alkyl, aryl, heteroaryl, alkenyland alkynyl, each of which may be optionally substituted.

In the embodiment where ROH is the nucleophile, and ROH is water (i.e. Ris hydrogen), the product is the carboxylic acid.

These 3-component reactions (i. CO; ii. ArX or alk-X; iii. nucleophilicspecie) may be intramolecular. That is to say that the nucleophilicspecie and the activated substrate are each moieties of a singlemolecule.

In intermolecular reactions, i.e. where the organic reactant and theactivated substrate are not moieties of a single molecule, the reactionmixture also contains an additional reactant. Suitable additionalreactants are selected from the group consisting of amines, alcohols,thiols, hydride ions, alkenes, alkynes, boric acids, boronic acids,carboxylate ions, malonate-type ions, enolate-type ions, azide ions,cyanide ions, halide ions, phosphines R₃P wherein R is aryl, heteroarylor alkyl, metal organic compounds.

Furthermore, in addition to the examples listed above which serve toactivate the substrate, X may be hydroxyl, such that the substrate is aprimary, secondary, or tertiary alcohol (Chaudhari et al, OrganicLetters, 2000, 2 (2), 203). In such embodiments, a halide promoterand/or an acid promoter may additionally be required. A halide promotermay be Li-halide (Chaudhari et al, 2000) wherein the corresponding haloderivative is a reaction intermediate. Within this embodiment, water maybe used as the nucleophile, in which case the corresponding carboxylicacid is the product. An alcohol, thiol, or amine may suitably be used asnucleophile so as to provide an ester, thioester, or amide,respectively.

Alternatively, in the suitable embodiment wherein X is hydroxyl, thehydroxyl may be converted in situ to its corresponding mesylate,triflate, phosphonate, tosylate, or boronic acid using methods known tothe person skilled in the art.

The catalyst is typically a catalyst involving Pd⁰/Pd^(II) orPd^(II)/Pd^(IV) catalytic cycles such as conventional neutral palladiumcomplexes such as PdCl₂(PPh₃)₂ or cationic complexes such asPd(PPh₃)₂(OTs)₂ or [Pd(PhCN)₂(PPh₃)₂][BF₄]₂. The catalyst mayalternatively be a palladium(II) complex containing chelating anionicpyridine-2-carboxylato and labile tosylato ligand such as the catalystdescribed by Chaudhari et al.

Type II reactions are intended to anticipate 3-component reactionsinvolving direct carbonylation (i.e. unactivated systems) of asubstituted aryl or optionally substituted heteroaryl and resulting inacylation of said substrate. The aryl may be substituted with adirecting group (Dir) so as to direct the regiochemistry of thecarbonylation. The directing group may be, for example, an oxazoline,oxazine, thioazine or pyridine group (Murai et al, J. Org. Chem., 2000,65, 1475). The directing group may also be an imine so as to form anoptionally substituted benzaldehyde imine. The product formed therefrommay serve as an intermediate in intramolecular aldol-type reactions. Insome selected examples where the aryl group contains heteroatoms nodirecting group is needed.

The aryl ring may be a heteroaryl. In a suitable embodiment, thecarbonylation may involve the direct carbonylation (of a C—H bond;unactivated system) of heteroaryl, without the use of a directing group.Quite obviously, the heteroaryl may also be substituted with a directinggroup.

An olefin other than ethylene may also be used, as maytrimethylvinylsilane, as the nucleophile. The olefin may be anoptionally substituted C₂₋₈-alkenyl.

The catalyst used in Type II reactions is typically Pd, V, Pt, Ru, andRh and suitable precatalysts are Pd(OAc)₂, (PPh)₃RhCl (Wilkinson'scatalyst), Ru₃(CO)₁₂, [RhCl(coe)₂]₂, RuH₂(CO)(PPh₃)₃ andCp*Rh(C₂H₃SiMe₃)₂.

Type IIIa reactions involve hydroformylations such as asymmetrichydroformylations. The metal-catalyst is typically selected from thegroup consisting of Pd, Pt, Rh, Ni, Cu, Cd, Zn, Ti, Sr, Ir, Co, and Ru,preferably selected from Pd, Pt, Rh, Ir, Co, Ru, and Ni, most preferablyin this reaction Type, the metal-catalyst selected is Rh, Ir, and Co.

The olefin may be of any length and may be optionally substituted.

The hydrogen source may be hydrogen gas or may be a solid source of H₂.One suitable embodiment of this reaction type involves the use of “solidH₂” wherein a reagent comprising a weakly acidic proton (such as forexample ethanol) and a hydride source are added to the reaction media.An alternative suitable embodiment uses H₂ gas and “solid CO” to avoidcomplexation.

Type IIIb reactions involve aminomethylation of an olefin. The reactionproceeds via the following process: hydroformylation (IIIa),condensation and hydrogenation.

The olefin may be of any length and may be optionally substituted.

The metal-catalyst in this reaction type is typically selected from thegroup consisting of Pd, Pt, Rh, Ni, Cu, Cd, Zn, Ti, Sr, Ir, Co, and Ru,preferably selected from Pd, Pt, Rh, Ir, Co, Ru and Ni., most preferablyselected from Rh, Ir, and Co.

Water may serve as the reductant in conjunction with CO. Alternatively,hydrogen may be provided. The hydrogen source may be hydrogen gas or maybe a solid source of H₂. One suitable embodiment of this reaction typeinvolves the use of “solid H₂” wherein a reagent comprising a weaklyacidic proton (such as for example ethanol) and a hydride source areadded to a the reaction media. An alternative suitable embodiment usesH₂ gas and “solid CO” to avoid complexation.

In type IVa reactions, R may be an organic species such as an aryl (Ar),such a phenyl, benzyl, or heteroaryl; alkyl such as C₁₋₁₂-alkyl;alkenyl, such as C₂₋₁₂-alkenyl; or alkynyl group such as C₂₋₁₂-alkynyl,each of which may be optionally substituted. The reaction may require ahalide promoter and/or an acid promoter (Chaudhari et al, 2000). Theproduct may be a regioisomer of those depicted so as to be the linearacids, esters, amides or thioesters. The use of a halide promoter mayreduce reaction times or improve regioselectivity.

The Pd-catalyst is typically a catalyst involving Pd⁰/Pd^(II) orPd^(II)/Pd^(IV) catalytic cycles such as conventional neutral palladiumcomplexes such as PdCl₂(PPh₃)₂ or cationic complexes such asPd(PPh₃)₂(OTs)₂ or [Pd(PhCN)₂(PPh₃)₂][BF₄]₂. The catalyst mayalternatively be a palladium(II) complex containing chelating anionicpyridine-2-carboxylato and labile tosylato ligand such as the catalystdescribed by Chaudhari.

R¹ may be selected from the group comprising of hydrogen (IVb),optionally substituted alkyl (IVc), optionally substituted aryl (IVd),halogen. (IVe), hydroxyl group (IVf), enamines (IVg), or ethers (IVh).

When the R¹ is an alkyl α-substituted with a halogen (IVd), said halogeneliminates, as known to the person skilled in the art. This embodiment(IVd) exemplifies subtypes of reactions wherein R¹ is modified duringthe reaction process.

In IVb type reactions, the nucleophile may, for example, be formic acid,resulting in the formation of the aldehyde.

The metal-catalyst is typically selected from the group consisting ofPd, Pt, Rh, Ni, Cu, Cd, Zn, Ti, or Sr, preferably selected from Pd, Pt,Rh and Ni, most preferably in this reaction type, Pd.

Type V reactions involve the “anti-Markovnikov” insertion of the carbonmonoxide unto propargylic systems to form substituted α,β-unsaturatedcarbonyls (such as in Alper et al, J. Org. Chem., 1999, 84, 2080). Thenature of the substituent depends on the selection of the nucleophile,some of which are shown supra. The product of this reaction is oftenintermediary and may continue to react such as to cyclise.

The substrate may be an alkynyl of any chain length. The alkynyl may beoptionally substituted and R1 may be a substituent as described supra.

The metal-catalyst is typically selected from the group consisting ofPd, Pt, Rh, Ni, Cu, Cd, Zn, Ti, and Sr, preferably selected from Pd, Pt,Rh and Ni, most preferably in this reaction Type, the metal-catalyst isselected from Pd and Rh.

Type VI reactions involve the “Markovnikov” carbonylation of conjugatedenynes to provide a conjugated diene (such as in Alper et al, J. Org.Chem., 1999, 84, 2080). The catalyst is typically selected from thegroup consisting of Rh, Pd, Co, Ir and Pt.

All reaction types (I-VI) comprise the steps of preparing a reactionmixture comprising a non-catalysing material generating CO in situ andexposing said reaction mixture to an energy source affording liberationof carbon monoxide from said CO generating material, wherein carbonmonoxide is involved in said reaction such that the carbon of saidcarbon monoxide is involved in bond formation to a non-metal during saidorganic reaction.

The reaction conditions (e.g. selection of catalyst) shown for each ofthe reaction types are merely to exemplify an embodiment within thereaction type. The catalyst may be selected from those known in the art.Additives may be required or preferred in embodiments of particularreaction types. The energy source may be tailored to the needs orfacilities available to the practitioner.

As stated the metal carbonyl is not complexed with or bonded to anon-metal prior to preparing said reaction mixture. The metal (M) isselected from elements which when bonded to CO, said CO-M bond istypically be weaker than C—CO bond in order for the energy barrier fortransferring CO to the substrate be favourable. The metal carbonyl isthe unique carbonyl source to the reaction mixture and is referred to asCO releasing compound to distinguish it from gaseous sources of CO.

The non-metal substrate can be bound to a polymer. Suitable suchpolymers are polystyrene, polyacryl amide, polyethylene glycol. Themetal carbonyl, M_(x)(CO)_(y) may comprise of transitions elements,Group I, II, III, IV, V, VI; VII or Group VIII metals (M), preferablytransition metals and may be tailored to the nature of the reaction, thereagents and/or any catalyst comprising the reaction mixture. Typically,the metal (M) of said metal carbonyl is selected from the groupcomprising of Mo, Fe, W, Mn, Cr, and Co, preferably Mo, Fe and Cr, mostpreferably Mo.

The metal carbonyl may exist as a complex of one or more metalscomplexed with one or more carbon monoxide molecules. Accordingly, inthe formula M_(x)(CO)_(y), x may be any integer, depending on the levelof the complex. Typically, x is selected from 1 to 10 such as 1 to 6,preferably selected from an integer from 1 to 4, such as 1, 2, 3, and 4.

Similarly, y is an integer whose value depends on the size of the metalcarbonyl complex. Typically, y is selected from 2 to 40 such as 2 to 24,preferably selected from an integer from 2 to 12. Y is an integergreater than x.

The metal carbonyl may be selected from those known to the personskilled in the art. The metal carbonyl may be selected from thenon-limiting group comprising of Mo(CO)₆, W(CO)₆, Mn₂(CO)_(g), Cr(CO)₆,and Co(CO)₈ or derivatives thereof, preferably Mo(CO)₆ and Ca(CO)₆,especially Mo(CO)₆.

Prior to preparing the reaction mixture, the metal carbonyl is notcomplexed with or bonded to the non-metal with which the carbon of saidcarbon monoxide is involved in bond formation. This offers the advantageof independently selecting the carbonyl source from the substrate. In asuitable embodiment of the method of the invention, a non-metal ligandmay be bonded to the metal carbonyl. However, this not only tends tolower the reactivity of the metal carbonyl but also lowers the capacityof CO-liberation.

The metal carbonyl may comprise of more than one metal so as to form a(M¹M²)_(x)(CO)_(y) complex.

In preferred embodiments, the method comprises the use of from 0.1 to10,000,000 molar equivalents (higher limit set for PET applications orsimilar for example) of the metal carbonyl, such as from 0.1 to 1000,0.25 to 100, 0.5 to 50 or 0.75 to 20 equivalents. Alternatively viewed,the method comprises the use of from 1 to 100 molar equivalents ofliberated carbon monoxide. As will be appreciated, the uniquestoichiometry of each metal carbonyl (e.g. the x to y ratio inM_(x)(CO)_(y)) determines the number of equivalents of of complex thatis required.

Preferably, the metal-carbonyl is of low toxicity.

The metal carbonyl, when exposed to an energy source, affords liberationof carbon monoxide in its gaseous form from said metal carbonyl, intothe reaction mixture.

A suitable non-catalysing compound generating CO in situ which can beused in the method according to the present invention is a formamide ofthe general formula IIHCONR₁R₂  IIwherein R₁ and R₂ independently can be H, linear or branched alkyl,optionally substituted, aryl or alkylaryl, wherein the alkyl grouppreferably contains 1 to 6 carbon atoms, such as methyl, ethyl, propyl,isopropyl, butyl, t-butyl, pentyl and hexyl. Each of these alkyl groupsmay be substituted with a halogen group, such as fluoro. The aryl groupis preferably phenyl and a suitable alkylaryl group is (C₁₋₆ alkyl)phenyl.

Two examples of suitable formamides of the general formula II areformamide itself, wherein R₁ and R₂ are H, and dimethyl formamide (DMF),wherein R₁ and R₂ both are methyl.

When a formamide of the formula II is used in the method according tothe present invention as a non-catalysing CO generating compound thereaction mixture in addition also contains imidazole or a substitutedimidazole, a metal catalyst and a strong base having a pKa value ofabout 15 or higher.

The formamide of the general formula II is used in amounts of 0.1 to10,000,000 molar equivalents, such as from 1 to 1,000, preferably 1 to100, most preferably 5 to 50 molar equivalents.

Examples of suitable metal catalysts are selected from those statedherein.

Examples of strong bases suitable to use in the reaction mixturetogether with the amide of formula II in the method according to thepresent invention are KOtBu, NaOtBu (pKa˜17), KO-iso-Pr, NaO-iso-Pr(pKa˜16.5), KOEt, NaOEt (pKa˜16), KOMe, NaOMe (pKa˜15), KOH, NaOH(pKa˜16), lithium diisopropylamide (LDA) and NaH (pKa˜35).

The energy source serves to provide sufficient energy to liberate acarbon monoxide molecule from the non-catalysing compound generating COin situ. The method according to the present invention comprises a stepof exposing a reaction mixture to a source of energy affordingliberation of carbon monoxide. Preferably, when the step of exposing thereaction mixture to an energy source is performed with the metalcarbonyl, the reaction mixture comprises the metal carbonyl and thenon-metal with which carbon monoxide is involved in bond formation.

In the method of the present invention the energy source is preferablyselected from thermal energy, sonic energy, ultraviolet irradiation,microwave energy, and radiofrequency, most preferably thermal energy andmicrowave energy, particularly microwave energy.

The efficiency of microwave flash-heating chemistry in dramaticallyreducing reaction times (from days and hours to minutes and seconds) isdemonstrated herein. It has been shown useful in other fields of organicchemistry but not in the types of reactions of the present invention. Inthe context of reactions types discussed herein, it is believed that theuse of microwaves will have a tremendous impact on the production rateof substance libraries. Thus, a further aspect of the present inventionrelates to a method for performing microwave-assisted reactionscomprising the steps of preparing a reaction mixture comprising anon-catalysing compound generating CO in situ; and exposing saidreaction mixture to sufficient microwave energy to afford liberation ofcarbon monoxide from said non-catalysing material generating CO in situ,wherein the carbon monoxide is involved in said reaction such that thecarbon of said carbon monoxide is involved in bond formation to anon-metal during said organic reaction. The liberating of carbonmonoxide is as its gaseous form into said reaction mixture.

Contrary to the case in conventional conductive heating, microwave heatis generated inside the bulk of the sample (in situ heating) and isdistributed from inside and out (no wall effects), causing the sample toheat up evenly and rapidly (up to 200° C. per second). Cooling begins assoon as the field is turned off (the reaction vessel is microwavetransparent). The homogeneous heating and the sharp difference intemperature profiles between microwave heating and traditional heatingcan, however, enable convenient high-temperature transformations, resultin less decomposition of temperature-sensitive products and inalternative product distributions.

As stated, other fields of chemistry have found advantages ofmicrowave-stimulated reactions. For instance, U.S. Pat. No. 4,279,722discloses the enhancement of the conversion of liquid hydrocarbonsderived from petroleum in a catalytic petroleum refinery process byexposing a mixture of hydrocarbons and catalyst to microwave in thefrequency range of about 2.5×10⁹ to 10¹² Hz. U.S. Pat. No. 5,215,634discloses a process for selectively converting methane and a hydratingagent to C₃ oxygenates. In particular, methane is reacted with water inthe presence of a nickel metal powder catalyst using microwaveirradiation to produce acetone and propanol. U.S. Pat. No. 5,411,649discloses selective production of ethane and ethylene in high yields byusing particular catalysts and microwaves for controlled oxidation. EP0742189 discloses production of an organo-nitrogen compound byirradiating a mixture of a catalyst, an organic compound and nitrogenwith microwaves. Finally, EP 0787526 discloses the enhancement ofcatalytic reaction rates at low temperatures by utilising microwaves andother techniques, such as simulates boiling, ultrasonication.

In a preferred embodiment of a method of the present invention, thereaction proceeds in a closed vessel such as a SmithProcessVial™ sealedwith, for example a Crymper™-seal. A closed vessel has as an advantageof requiring less of the metal carbonyl than an open vial. Nonetheless,in a suitable embodiment of the invention wherein the metal carbonylcompound is used as CO generating material, the reaction proceeds in anopen vessel.

In a non-binding interpretation of the mechanism by which the advantagesof preferred embodiments of the method of the invention proceed, thetemperature and CO-liberation rate seem to have a nearly exponentialrelationship. That is to say that for low pressure applications (i.e.reactive applications not dependent on high pressures; useful forapplications with open vessels) one can have a low temperature (150° C.or below), while for slower reactions, higher temperatures arenecessary. Moreover, there are indications that water (and to someextent a coordinating solvent, preferably with high oxygen content)facilitates a smooth liberation of the CO from the metal carbonyl.

Examples 1 and 2 illustrate that the use of microwave energy incombination with the use of the metal carbonyl as CO generating compoundis particularly amenable to at least reaction type I. It is anticipatedthat microwave energy is amenable to all reaction types of the presentinvention. FIG. 2 illustrates an example of reaction type I wherein anaryl bromide is carboxylated to an amide or alternatively to acarboxylic acid. FIG. 2 further illustrates the carboxylation of an aryliodide to its corresponding amide. The CO releasing compound in theseillustrative reactions was molybdenum hexacarbonyl. The catalyst, asstated, may be selected from a variety of metal and metal complexes.This is well illustrated in contrasting Example 1 and 2 wherein in theformer the highly complexed palladacycle is used whereas in the latter,simple palladium on carbon is used. Full conversion is experienced inall cases. The toluene derivatives, which serve as substrates, areconsidered to be very difficult substrates by conventional carbonylationmethodologies. The positive results shown herein clearly show theadvantages of the method of the invention. Less problematic substratesgive even better results. The weakly nucleophile aniline has alsoyielded positive results.

Example 3 illustrates that the use of microwave energy in combinationwith the use of the metal carbonyl M_(x)(CO)_(y) as CO releasingcompound is particularly amenable to at least reaction type III and isanticipated to be amenable to all reaction types. Wilkinson's catalystwas found to be a suitable catalyst for the invention.

In the preferred embodiment of the method, wherein microwave energy isused as the energy source, reaction times are typically short. Thisadvantageous feature may be due to the rate at which the temperature ofthe reaction mixture increase or as a result of putative microwaveeffects.

Exposure to the microwave energy is preferably for less than 1 hour,preferably for less than 20 minutes.

The temperature of the reaction mixture, upon exposure to the energysource when using a metal carbonyl compound as the CO generatingcompound must be such that the temperature is raised to at least 50° C.,preferably at least 100° C., most particularly to at least 150° C.

In suitable embodiments of the invention, the reaction mixture comprisesa metal-carbonyl of the general formula I, a non-metal with which thecarbon of CO (of the metal-carbonyl) bonds, and a metal-catalyst. Inother suitable embodiments the reaction mixture comprises a formamide ofthe general formula II, an imidazole or a substituted imidazole, a metalcatalyst and a strong base.

The metal catalyst typically comprises of a metal with a ligand and maybe as described supra. The ligands, if any, may be selected from thearray of ligands known to the person skilled in the art.

The metal is typically selected from Pd, Pt, Rh, Ni, Cu, Cd, Zn, Ti, Sr,Co, Ir, Ru, Ta, W, Fe, Re, or Os, preferably selected from Pd, Pt, Rh,Co, Ir, Ru and Ni.

The metal catalyst is most preferably selected from a Pd⁰, Pd^(II),Pd^(IV), Pt⁰, Pt^(II), Pt^(IV), Ni⁰, Ni^(I), N^(II), Ni^(III), Rh⁰,Rh^(I), Rh^(II), Rh^(III), Co⁰, Co^(I), Co^(II), Co^(III), Ir⁰, Ir^(I),Ir^(II), Ir^(III) species, or of those of approximately the sameoxidation state or potential.

The amount of metal catalyst may vary with the reaction type, thereactivity of the substrate, the nature of the metal carbonyl, theenergy source, and other reaction conditions such as the solvent andconcentration of the reaction mixture. The metal catalyst is typicallypresent in molar equivalents of at most 0.9, such as at most 0.7,preferably at most 0.5, such as 0.4, 0.3, 0.2, 0.1 molar equivalents,most preferably at most 0.05 molar equivalents, such as at most 0.02 orat most 0.01 molar equivalents.

The reaction mixture typically comprises a nucleophilic species. Thus,the reaction mixture may comprise of a non-catalysing compoundgenerating CO in situ, a non-metal with which the carbon of CO bonds, ametal-catalyst, and a electrophilic species. Alternatively, such as inthe case of hydroformylation reactions, the reaction mixture maycomprise of a non-catalysing compound generating CO in situ, ametal-catalyst, and a non-metal comprising a moiety with which thecarbon of CO bonds and a moiety with nucleophilic character. That is tosay that the nucleophilic species may be a separate component or may becomprised in the non-metal component. This may vary on whether thereaction comprises an intramolecular coupling step or an intermolecularcoupling step.

The present invention has overcome the trouble of using gas incombinatorial chemistry reactions such as carbonylations by applying acompound releasing CO, which upon perturbation liberates enough gas insitu for the reaction to take place. Moreover, the short reaction timesassociated with the method are further amenable to combinatorialchemistry. Reaction times are particularly significantly reduced whenmicrowave energy is used as the energy source. The non-catalysingcompound releasing CO may be selected according to the handling needsand should have low toxicity, such as Mo(CO)₆.

The present invention therefore is amenable to the preparation ofchemical libraries through the combinatorial chemistry. Thus, thepresent invention further relates to a method of preparing chemicallibraries comprising the steps of preparing a reaction mixturecomprising a non-catalysing compound generating CO in situ and exposingsaid reaction mixture to an energy source affording liberation of carbonmonoxide from said CO releasing compound, wherein carbon monoxide isinvolved in said reaction such that the carbon of said carbon monoxideis involved in bond formation to a non-metal during said organicreaction.

The non-catalysing compound generating CO in situ suitably can be ametal carbonyl of the general formula I or an formamide of the generalformula II as described above. In order to provide the greatflexibility, it is most preferred that in the area of combinatorialchemistry for the preparation of chemical libraries, the metal carbonylis not complexed with or bonded to the non-metal (to which CO isinserted) prior to preparing said reaction mixture.

The flexibility, safety, and applicability to various reaction typesrenders the method particularly amenable to a kit for combinatorialprocesses. Thus, another aspect of the present invention is a kitcomprising a selection of one or more non-catalysing compoundsgenerating CO in situ such as metal carbonyls of formula I or formamidesof formula II and/or samples tubes and/or seals ready to use forapplying the method of the invention.

The method of the invention is further illustrated by the followingexamples, which are not intended to limit the scope of the invention.

EXAMPLES Examples 1-2

Type I: Carbonylation

The reactions and the results of Examples 1 and 2 are shown in FIG. 2.

General Microwave Procedure for the Synthesis of Amides 2. [Mo(CO)₆](30.0 mg, 0.114 mmol) and 1.375 mL of a fresh toluene solution ofpalladacycle (8.0 mg, 8.5 μmol) and BINAP (14.0 mg, 22.0 μmol), werecharged into a Smith Process Vial (a microwave-tube). A teflon-coatedstirring bar was added. Utilizing the SmithSynthesizer 0.200 mL 4.0 MK₂CO₃(aq), 1.00 mL diglyme, 0.290 mmol amine and aryl halide (0.229mmol, 0.100 mL of a stock solution of 4.59 mmol aryl halide in 2.00 mLdiglyme) were dispensed into the microwave tube. The tube was sealed(Crymper-seal) and the mixture was heated by microwaves at 150° C. for15 minutes. The mixture turned black during irradiation. After cooling,the reaction mixture was filtrated and concentrated at reduced pressure.The amide 2 was isolated by flash-chromatography.

Instead of the palladacycle and BINAP combination, corresponding amountsof 10% Pd/C (18.1 mg) were used with aryl iodides. Pd(OAc)₂ (3.8 mg)performed equally well with aryl iodides.

Note. With Pd/C, an alternative fast, but less efficient way ofisolating products 2 (˜10-15% lower yields), was to add HCl (2 mL of 2 Mconcentration) and 3 mL of diethyl ether to the reaction mixture afterirradiation. The mixture was shaken once and the ether phase was saved.Evaporation gave pure 2.

Microwave Procedure for the Synthesis of p-Methyl Benzoic Acid 3.[Mo(CO)6] (30.0 mg, 0.114 mmol) and 10% Pd/C (18.1 mg, 17.0 μmol) werecharged into a Smith Process Vial (a microwave-tube). A teflon-coatedstirring bar was added. Utilizing the SmithSynthesizer 0.200 mL 4 MK₂CO₃(aq), 0.700 mL diglyme, 0.300 mL ethylene glycol and p-tolyl iodide(0.229 mmol, 0.100 mL of a stock solution of 1.00 g (4.59 mmol) p-tolyliodide in 2.00 mL diglyme) were dispensed into the microwave tube. Thetube was sealed (Crymper-seal) and the mixture was heated by microwavesat 150° C. for 15 minutes. The mixture turned black during irradiation.Thereafter, 1 mL of 12 M HCl(aq) was added to the reaction mixture. Thereaction mixture gets warm! The cold crude acidic mixture was extracted2-3 times with diethyl ether. The separated diethyl ether phases wassubsequently extracted twice with 2 M NaOH(aq). Finally, the carboxylicacid 3 was precipitated by addition of 12 M HCl(aq) to the combinedNaOH(aq)-phases and extracted into diethyl ether. Evaporation of thediethyl ether solution afforded pure 3.

Example 3

The Reaction of Example 3 is Shown in FIG. 3.

Type III: Hydroformylation

Mo(CO)₆ (30 mg, 0.11 mmol), NaH (60%, 16 mg, 0.40 mmol) and Wilkinsonscatalyst (10 mg, 11 μmol) were measured into a Smith Processing Vials™microwave-tube. A teflon-coated stirring bar was added. Utilising theSmith Synthesizer™ styrene (36 ml, 0.31 mmol), 1.200 mL Diglyme and0.400 mL Ethylene glycol were dispensed into the microwave tube. Thetube was sealed (Crymper™-seal). The mixture was subjected to microwavesso that the temperature was 170° C. for 8 minutes. The mixture thenturned black. 2 mL of water and 3 mL of ether was added using the SmithSynthesizer™ dispenser. The mixture was shaken and filtrated. Analysiswas performed by GC-MS.

Examples 4-9

The Results and Products of Examples 4-9 are Shown in FIGS. 4 and 5.

Type I: Carbonylation of Aryl Iodides

General Microwave Procedure for the Synthesis of Esters 3.

A SmithProcessingVial™ with a teflon coated stirrer bar was charged withmolybdenum hexacarbonyl (33 mg, 0.125 mmol) and palladium on charcoal(12.5 mg, 10% Pd/C). Diglyme (500 μL), diisopropylethylamine (185 μL,1.0 mmol), alcohol 2 (500 μL, 3.5-6.7 mmol) and aryliodide 1 (0.25 mmol)were thereafter added. The vial was sealed with a Crymper™ seal and thereaction system was mixed manually to a suspension. The reaction washeated by microwave irradiation to 160° C. for 15 min (3a, 3b 5 min)with a Smith Synthesizer™. After cooling, the reaction mixture wasevaporated and filtered through a short silica plug with dichloromethaneas eluent. Analysis was performed by GC-MS and ¹H-NMR. The isolatedproducts 3 were >95% pure by capillary GC-MS.

Formamide of the General Formula HCONR₁R² (II) as CO Generating Compound

The results and reactions of these examples are shown in FIG. 6 andtables 1-6.

Type I: Carbonylation.

General procedure—A SmithProcessVial™ was charged with 0.75 mmol ofbromide, 3 mmol of amine/alcohol, 0.038 mmol of Pd(OAc)₂, 0.038 mmol ofDPPF, 0.75 mmol of imidazole, 1.13 mmol of potassium tert-butyl oxideand 1 ml of DMF. The reaction mixture was flushed with nitrogen and thecap was tightened thoroughly and then exposed to microwave irradiationfor the corresponding time. The reaction tube was allowed to cool toroom temperature and the mixture was extracted with 100 ml of ethylacetate, the organic layer was washed with water (2×50 ml) and brine,dried over potassium carbonate and the solvent was removed under reducedpressure. The residue was purified on silica gel.

The slightly electron rich 4-toluylbromide and the primary benzylaminewas used as substrate to investigate the Heck carbonylation reactionwith DMF as liquid source of carbon monoxide. The different reagents inthe reaction were investigated for their importance for the result(Table 1) and the reaction mixtures were analyzed on GC/MS. First theligand Dppf was excluded in the reaction (Entry 2). The amide 3 wasformed but the pressure in the reaction vessel was too high and themicrowave cavity ended the heating prematurely. This is most likely dueto the decomposition of the catalyst. Palladium black is formed whichhave higher susceptibility of microwave irradiation and thereforeproduce hotspots in the reaction vessel, and the reaction temperature isnot controllable. When the imidazole was excluded from the reactionmixture (Entry 3) no carbonylation reaction product was formed. Themajor product was derived from a Buchwald type amination of the bromide.When the reaction was performed with a weaker base, K₂CO₃, no amideproduct was detected in the reaction mixture and most of the bromide wasrecovered. Without the palladium catalyst the formamide product ofbenzylamine was formed as the major product. This product is most likelyderived from nucleofilic attack of the amine on DMF (Entry 5). Withdimethylacetamide (DMAc) as solvent instead of DMF no carbonylationproduct was detected (entry 6). In the recent publication by Schnyder etal. they report DMAP as base for decomposition of DMF. When DMAP wasused under our condition (entry 7) no desired carbonylation product wasyielded, the major product was the resulting secondary amine.

The ligand was shown to be important for the stability of the catalystin the reaction. Different ligands were screened to optimize thereaction, the results are summarized in Table 2. All the chelatingligands gave the desired product (3) but the mono-dentate ligands werenot efficient in this reaction and gave no product. Dppf gave the bestresult in under these conditions and a yield of 63% of compound 3 wasisolated.

In the original reaction 1 eq. of the base KOtBu was used. By increasingthe amount to 1.5 eq. the yield could be improved to 73%, but thereaction yield was not improved by further addition of the base (table3). By lowering the amount of catalyst in the reaction from 5% to 2%,the yield dropped to 47% (Entry 4, Table 3).

The influence of the reaction time and the temperature was investigatedand the results are summarized in Table 4. A shorter time gave a loweryield but a more dramatic effect was observed when lowering the reactiontemperature. At 150° C. only a very small amount of the product could beisolated. When increasing the temperature to 190° C. a slightly betterresult was observed.

The pressure of the reaction was monitored during the reactions. Apressure of 1.7 Bar was formed in the sealed vessels after 15 min. Theorigin of the pressure is most likely due to the evaporation of the DMF,although the contribution of the formed CO_((g)) could not bedetermined. When heating a sample of pure DMF the Pressure reached 2.2Bar with the same temperature and time. The higher pressure formed inpure DMF could be that no CO_((g)) is consumed in this system.

The high temperature required in the reactions, 180-190° C., is easilyobtained in the microwave cavity. In a conventional oil-bath thistemperature is not so practical. A reaction (table 5 entry 1) wastherefor performed with conventional heating at 130° C. but with alonger reaction time, 10 h. This gave the desired product in a moderateyield, 25%.

The scope of the reaction was demonstrated using 5% Pd(OAc)₂, 5% Dppf, 1eq. imidazole, 3eq. amine, and 1.5 eq. KOtBu in DMF as solvent. Avariety of amines and aryl bromides were converted to the correspondingamides, here shown in Table 5. The slightly electron rich 4-bromotoluenewas reacted with primary, secondary, and anilinic amines (entries 1-4).

All of the reactions gave a good yield, and surprisingly the secondaryamine morpholine gave a very good yield. With out an external amine thedimethyl amide was formed, where the amine part of the amide wasprovided from the DMF (entry 4). In entry 5 formamide was used assolvent instead of DMF. This gave the unsubstituted amide in good yield(74%). This provides a very convenient method for formation of primaryamides without the use of ammonia. The influence of the electronic andsteric properties of the aryl bromide was investigated in entry 6-9.With the slightly more steric 2-bromotoluene the reaction needed alonger time for completion, but resulted in an excellent yield (94%).The electron neutral and electron rich bromides, entireties 7,8, bothgave good yields, although the 4-methoxybenzyl bromide required 20 minfor total consumption of the starting material. When applying theelectron deficient 4-cyanobenzyl bromide no desired product was detectedin the reaction mixture (entry 9). The secondary amine derived from thecompeting amination reaction, which is a fast reaction with electrondeficient aryl bromides, was the major product in this reaction. In theabsence of any bromide the benzylformamide was formed in a good yield,entry 10, this reaction is less likely to be palladium catalyzed.

To further broaden the scope of the reaction a primary alcohol was usedin the reaction instead of an amine. The resulting benzyl ester wasformed in a good yield (Table 6).

Experimental Section

General considerations—¹H and ¹³C NMR spectra were recorded at 270.2 and67.9 MHz, respectively. Chemical shifts are given as δ values (ppm)downfield from tetramethylsilane. Flash column chromatography wasperformed on silica gel 60 (0.04-0.063 mm). Thin-layer chromatographywas performed on precoated silica gel F-254 plates (0.25 mm) andvisualized with UV light or ninhydrin in ethanol. The palladium acetatewas bought from Merk Company, BINAP from Aldrich, and DPPF from StreamChemicals Company. All other chemicals were purchased from Aldrich orFluka and were used directly without further purification. All microwavereactions were carried out in SmithProcessVial. Microwave heating wascarried out with Smith creator and Smith Synthesizer from PersonalChemistry. It is not recommended to repeat these reactions in amultimode domestic microwave oven producing no uniform irradiation.GC-MS was performed with a HP-5890 series II equipped with a HP-5971Mass selective detector, and a HP-1 capillary column using 70-305ssprogram gradient. TABLE 1 Importance of the reagents. Relative Peakheight on GC/MS Entry Solvent Pd(OAc)₂ Dppf Imidazole Base Amide 3 1 DMFYes Yes Yes KOtBu 80 2 DMF Yes No Yes KOtBu 44^(a) 3 DMF Yes Yes NoKOtBu  0^(b) 4 DMF Yes Yes Yes K₂CO₃  0 5 DMF No Yes Yes KOtBu  0^(c) 6DMAc Yes Yes Yes KOtBu  0 7 DMF Yes Yes No (DMAP) KOtBu  0^(b)^(a)The pressure of the reaction was to high to control and the reactionwas terminated.^(b)The major product was the product derived from amination reaction.^(c)Formylation of the amine was the major product.

TABLE 2 Ligand Screening. Entry Ligand Isolated Yield 1 Dppf 63 2 Dppp37 3 P(o-Tol)₃ — 4 Binap 49 5 PPh₃ —

TABLE 3 Amount of Base and Catalyst. Entry Ekv. Base mol % Pd(OAc)₂Isolated Yield 1 1 5 63 2 1.5 5 73 3 2 5 70 4 1.5 2 47

TABLE 4 Time and Temperature variation. Entry Time (Min) Temp (° C.)Isolated Yield 1 10 180 53 2 15 180 73 3 15 150 3 4 15 190 76

TABLE 5 Aryl Time Temp Isolated Entry Bromide Amine Product (min) (° C.)Yield (%) 1

15 190 76 2

20 190 77 3

20 190 83 4

—

15 180 59 5

—^(a)

15 180 74 6

20 190 94 7

15 190 82 8

20 190 70 9

20 190   0^(a) 10 —

20 190 67

TABLE 6 Aryl Time Temp Yield Entry Bromide Amine Product (min) (° C.)(%) 1

15 190 71

N-Benzyl-4-methyl-benzamide (entry 1, table 5), With hexane/acetone(4:1) as eluent gave 128.6 mg of the entitled compound as a white solid.IR(neat) ν 1638 cm⁻¹; MS m/z 225(M⁺); ¹H NMR (CDCl₃) δ7.63 (d, J=8.1 Hz,2H), 7.27-7.12 (m, 7H), 6.52 (brs, 1H), 4.55 (d, J=5.8 Hz, 2H), 2.31 (s,3H); ¹³C NMR (CDCl₃) δ 167.3, 141.9, 138.2, 131.4, 129.2, 128.7, 127.8,127.5, 126.9, 43.9, 21.4.

4-Methyl-N-phenyl-benzamide (entry 2, table 5), With hexane/acetone(3:1) as eluent gave 122.7 mg of the entitled compound as a white solid.IR (neat) ν 1652 cm⁻¹; MS m/z 211 (M⁺); ¹H NMR (CDCl₃) δ 7.92 (brs, 1H),7.78 (d, J=8.1 Hz, 2H), 7.66 (d, J=7.7 Hz, 2H), 7.39-7.11 (m, 5H), 2.41(s, 3H); ¹³C NMR (CDCl₃) δ 165.7, 142.3, 138.0, 132.0, 129.3, 129.0,127.0, 124.4, 120.1, 21.5.

4-methyl-N-morpholine-benzamide (entry 3, table 5), With CHCl₃/MeOH(35:1) as eluent on aluminaoxide gave 127.5 mg of the entitled compoundas a pale yellow liquid which contained 10% of dimehtyl-4methylbenzamidedetermined by ¹H NMR. IR (neat) ν 1649 cm⁻¹; MS m/z 204(M⁺); ¹H NMR(CDCl₃) δ7.17-7.10 (m, 4H), 6.52 (brs, 1H), 3.70-3.08 (m, 8H), 2.22 (s,3H); ¹³C NMR (CDCl₃) δ 170.5, 139.9, 132.2, 129.0, 128.8, 127.1, 66.8,21.1.

N-benzyl-2-methyl-benzamide (entry 6, table 5), With hexane/acetone(3:1) as eluent gave 158.3 mg of the entitled compound as a white solid.IR (neat) ν 1627 cm⁻¹; MS m/z 225(M⁺); ¹H NMR (CDCl₃) δ 7.36-7.11 (m,9H), 6.24 (brs, 1H), 4.59 (d, J=5.9 Hz, 2H), 2.43 (s, 3H); ¹³C NMR(CDCl₃) δ 169.9, 130.9, 129.8, 128.7, 127.7, 127.5, 126.6, 125.6, 43.8,19.8.

N-Benzyl-4-methoxy-benzamide (entry 8, table 5), With hexane/acetone(3:1) as eluent gave 125.7 mg of the entitled compound as a white solid.IR (neat) ν 1632 cm⁻¹; MS m/z 241(M⁺); ¹H NMR (CDCl₃) δ 7.78-7.75 (m,2H), 7.34-7.28 (m, 5H), 6.90-6.86 (m, 2H), 6.68 (brs, 1H), 4.59 (d,J=5.8 Hz, 2H), 3.81 (s, 3H). ¹³C NMR (CDCl₃) δ 166.8, 162.1, 138.4,128.7, 128.6, 127.8, 127.4, 126.5, 113.6, 55.3, 43.9.

Benzyl-4-methylbenzoate (entry 1, table 6), With hexane/acetone (5:1) aseluent gave 120.8 mg of the entitled compound as a colorless liquid. IR(neat) ν 1716 cm⁻¹; MS m/z 226(M⁺); ¹H NMR (CDCl₃) δ 7.99 (d, J=8.2 Hz,2H), 7.44-7.25 (m, 7H), 5.37 (s, 2H), 2.40 (s, 3H); ¹³C NMR (CDCl₃) δ166.5, 143.7, 136.1, 129.7, 129.0, 128.5, 128.1, 128.0, 127.3, 66.5,21.7.

1. A method of performing a one-pot organic reaction, which includescarbon monoxide as reactant and does not use of an external CO gassource, which comprises preparing a reaction mixture containing anon-catalysing solid or liquid CO releasing compound, a non-metalsubstrate compound and a metal catalyst; and exposing said reactionmixture to an energy source to release carbon monoxide from the COreleasing compound, wherein carbon atoms of the released carbon monoxideform a bond with the non-metal substrate compound, wherein thenon-catalysing CO releasing compound is a formamide of the generalformula II,HCONR₁R₂ wherein R₁ and R₂ independently can be H, or an optionallysubstituted, linear or branched alkyl, aryl or alkylaryl group.
 2. Themethod according to claim 1, wherein R₁ and R₂ independently are a C₁₋₆alkyl group or H.
 3. The method according to claim 1, wherein theformamide is used in amounts of 0.1 to 10,000,000 molar equivalents. 4.A method of preparing a chemical library which comprises preparing areaction mixture containing a non-catalysing solid or liquid COreleasing compound, a non-metal substrate compound and a metal catalyst;and exposing the reaction mixture to an energy source to release carbonmonoxide from the CO releasing compound, wherein the carbon atoms of thereleased carbon monoxide form a bond with a non-metal substratecompound.
 5. The method according to claim 4, wherein the non-catalysingCO releasing compound is a formamide of the general formula I,HCONR₁R₂ wherein R₁ and R₂ independently can be H, or an optionallysubstituted, linear or branched alkyl, aryl or alkylaryl group.
 6. A kitfor organic reactions including CO as reactant comprising a one or moresolid or liquid CO releasing compounds, selected from metal carbonyls ofthe general formula I,M_(x)(CO)_(y) wherein M is a metal, x is an integer, y is an integer, orformamides of the general formula II,HCONR₁R₂ wherein R₁ and R₂ independently can be H, or an optionallysubstituted, linear or branched alkyl, aryl or alkylaryl group.
 7. Themethod according to claim 3, wherein the formamide is used in amounts of1 to 1,000 molar equivalents.